Farnesyl transferase inhibitors, preparation thereof, and pharmaceutical compositions containing same

ABSTRACT

Novel farnesyl transferase inhibitors of general formula (I) ##STR1## preparation thereof and pharmaceutical compositions containing same. In general formula (I), R 1  is Y--S--A 1  -- (where Y is a hydrogen atom, an amino acid residue, a fatty acid residue, an alkyl or alkoxycarbonyl radical, or a radical R 4  --S--, where R 4  is a C 1-6  alkyl radical optionally substituted by a phenyl radical, or a radical of general formula (II), ##STR2## wherein A 1 , X 1 , Y 1 , R&#39; 2 , R&#39; 2 , X 2 , Y 2 , R 3 , R&#39; 3  and R are as defined below, and A 1  is a C 1-4  alkylene radical optionally α-substituted in the &gt;C(X 1 ) (Y 1 ) grouping by an amino, alkylamino, alkanoylamino or alkoxycarbonylamino radical); X 1  and Y 1  are each a hydrogen atom or, taken together with the carbon atom to which they are attached, a &gt;C═O grouping; R 2  is a straight or branched C 1-4  alkyl radical optionally substituted by a cyclohexyl radical; R&#39; 2  is hydrogen or alkyl; X 2  and Y 2  are each a hydrogen atom or, taken together with the carbon atom to which they are attached, a &gt;C═O grouping; R 3  is a C 1-4  alkyl radical optionally substituted by hydroxy, alkoxy, mercapto, alkylthio, alkylsulphinyl or alkylsulphonyl, with the proviso that, when R 3  is an alkyl radical substituted by a hyroxy, alkoxy, mercapto, alkylthio, alkylsulphinyl or alkylsulphonyl, with the proviso that, when R 3  is an alkyl radical substituted by a hydroxy radical, R 3  may form a lactone with the α-carboxy radical; R&#39; 3  is hydrogen or alkyl; X is an oxygen or sulphur atom; and R is a hydrogen atom or an optionally substituted alkyl radical or an optionally substituted phenyl radical. These novel products have anticancer properties.

BACKGROUND OF THE INVENTION

The inhibition of farnesyl transferase, and consequently of thefarnesylation of the ras protein, blocks the capacity of the mutated rasprotein to transform normal cells into cancerous cells.

The C-terminal sequence of the ras gene contains the unit "CAAX" or"Cys-Aaa₁ -Aaa₂ -Xaa", in which Aaa represents an aliphatic amino acidand Xaa represents any amino acid.

It is known that tetrapeptides with a CAAX sequence can inhibit thefarnesylation of the ras protein. For example, peptide inhibitors offarnesyl transferase, Cys-Aaa₁ -Aaa₂ -Xaa, which are more particularlyrepresented by the peptides Cys-Val-Leu-Ser, Cys-Val-Ile-Met andCys-Val-Val-Met which manifest their inhibitory activity atconcentrations in the region of 10⁻⁶ M or 10⁻⁷ M, have been described inPCT Application WO 91/16340 and in Application EP 0,461,869.

SUMMARY OF THE INVENTION

The present invention relates to the new farnesyl transferase inhibitorsof formula: ##STR3## to their preparation and to the pharmaceuticalcompositions which contain them.

It has now been found, and this forms the subject of the presentinvention, that the peptides of general formula (I) manifest theirinhibitory activity (IC₅₀) at concentrations of the order of 10⁻⁸ M.

In the general formula (I), R₁, represents a radical of general formulaY--S--A₁ -- in which Y represents a hydrogen atom or an amino acidresidue or a fatty acid residue or an alkyl or alkoxycarbonyl radical oran R₄ --S-- radical in which R₄ represents an alkyl radical containing 1to 6 carbon atoms, optionally substituted by a phenyl radical, or aradical of general formula ##STR4## in which A₁, X₁, Y₁, R₂, R'₂, X₂,Y₂, X, R₃, R'₃ and R are defined as below, and A₁ represents a straightor branched alkylene radical containing 1 to 4 carbon atoms, optionallysubstituted at the position α to the >C(X₁) (Y₁) group by an aminoradical, an alkylamino radical containing 1 to 4 carbon atoms, analkanoylamino radical containing 1 to 4 carbon atoms or analkoxycarbonylamino radical in which the alkyl part contains 1 to 4carbon atoms,

X₁ and Y₁ each represent a hydrogen atom or form, together with thecarbon atom to which they are bonded, a >C═O group,

R₂ represents a straight or branched alkyl radical containing 1 to 4carbon atoms, optionally substituted by a cyclohexyl radical,

R'₂ represents a hydrogen atom or a straight or branched alkyl radicalcontaining 1 to 6 carbon atoms,

X₂ and Y₂ each represent a hydrogen atom or form, together with thecarbon atom to which they are bonded, a >C═O group,

R₃ represents a straight or branched containing alkyl radical containing1 to 4 carbon atoms, optionally substituted by a hydroxyl radical, analkoxy radical containing 1 to 4 carbon atoms, a mercapto radical, analkylthio radical containing 1 to 4 carbon atoms, an alkylsulphinylradical containing 1 to 4 carbon atoms or an alkylsulphonyl radicalcontaining 1 to 4 carbon atoms, it being understood that, when R₃represents an alkyl radical substituted by a hydroxyl radical, R₃ canform a lactone with the carboxyl radical at the α position,

R'₃ represents a hydrogen atom or a straight or branched alkyl radicalcontaining 1 to 6 carbon atoms,

X represents an oxygen or sulphur atom, and

R represents a hydrogen atom or an alkyl radical, optionally substitutedby an alkoxy radical containing 1 to 4 carbon atoms, an alkylthioradical containing 1 to 4 carbon atoms, an alkylsulphinyl radicalcontaining 1 to 4 carbon atoms, an alkylsulphonyl radical containing 1to 4 carbon atoms, a phenyl radical, a phenoxy radical, a phenylthioradical, a phenylsulphinyl radical, a phenylsulphonyl radical, analkylamino radical containing 1 to 4 carbon atoms or a dialkylaminoradical in which each alkyl part contains 1 to 4 carbon atoms, or aphenyl radical, optionally substituted by one or a number of atoms orradicals, which are identical or different, chosen from halogen atomsand alkyl, alkoxy, alkylthio or alkanoyl radicals containing 1 to 4carbon atoms.

More particular embodiments of the invention are compounds of formula Iwherein

R₁ represents a radical of formula Y--S--A₁ -- in which Y represents ahydrogen atom or a lysine residue or a fatty acid residue containing upto 20 carbon atoms and

A₁ represents an ethylene or propylene radical optionally substituted byan amino radical,

X₁ and Y₁ each represent a hydrogen atom or form, together with thecarbon atom to which they are bonded, a >C═O group,

R₂ represents an isopropyl, 1-methylpropyl, tert-butyl orcyclohexylmethyl radical,

R'₂ represents a hydrogen atom or a methyl radical,

X₂ and Y₂ each represent a hydrogen atom or form, together with thecarbon atom to which they are bonded, a >C═O group,

R₃ represents a methyl or ethyl radical substituted by a hydroxyl,methoxy, mercapto, methylthio,

methylsulphinyl or methylsulphonyl radical,

R'₃ represents a hydrogen atom or a methyl radical,

X represents an oxygen atom, and

R represents a hydrogen atom or an alkyl radical containing 1 to 4carbon atoms, optionally substituted by an alkoxy radical, or a phenylradical.

More particularly still,

R₁ represents a radical of formula Y--S--A₁ -- in which Y represents ahydrogen atom and A₁ represents an ethylene or propylene radicaloptionally substituted by an amino radical,

X₁ and Y₁ each represent a hydrogen atom or form, together with thecarbon atom-to which they are bonded, a >CO group,

R₂ represents an isopropyl, 1-methylpropyl, tert-butyl orcyclohexylmethyl radical,

R'₂ represents a hydrogen atom,

X₂ and Y₂ each represent a hydrogen atom or form, together with thecarbon atom to which they are bonded, a >C═O group,

R₃ represents a methyl or ethyl radical substituted by a hydroxyl,methoxy, mercapto or methylthio radical,

R'₃ represents a hydrogen atom, and

R represents a hydrogen atom or an alkyl radical containing 1 to 4carbon atoms.

The products of general formula (I) in which R₁ represents a2-mercaptoethyl or 1-amino-2-mercaptoethyl radical, X₁ and Y₁ eachrepresent a hydrogen atom or form, together with the carbon atom towhich they are bonded, a >CO group, R₂ represents an isopropyl radical,X₂ and Y₂ each represent a hydrogen atom or form, together with thecarbon atom to which they are bonded, a >C═O group, R'₂ represents ahydrogen atom, R₃ represents a 2-(methylthio)ethyl or2-(methylsulphinyl)ethyl radical, R'₃ represents a hydrogen atom and Rrepresents a hydrogen atom are very particularly advantageous.

The present invention also relates to the stereoisomeric forms of theproducts of general formula (I). The amino acid residues represented byR₁ C(X₁)(Y₁), R₂ CH(NR'₂) C(X₂) (Y₂)! and R₃ CH(NR'₃)CO--OH preferablyhave the configuration of the natural amino acids.

The present invention also relates to the inorganic or organic salts,and the esters, of the products of general formula (I).

According to the invention, the new products of general formula (I) canbe obtained by synthesis on a solid phase using a"9-fluorenylmethoxycarbonyl (FMOC)" synthesis strategy. In this case,the thiol groups are protected with trityl or acetamidomethyl groups,the amine functional groups with Boc (t-butoxycarbonyl) groups and theacid functional groups in the t-butyl ester form, the alcohol functionalgroups with t-butyl groups and the amide and imidazole functional groupswith trityl groups. The synthesis can be carried out on a resin confinedin 3 cm³ solid-phase extraction syringes made of high densitypolyethylene equipped with Teflon filters. The syringes are mounted on atwo-way Teflon valve and are closed by a disposable high densitypolyethylene finned plug. Agitation of the syringes is carried out on arotary device for haemolysis tubes. The washing and filtering operationsare carried out on a solid-phase extraction work station.

The syntheses are then carried out on 50 μmol of resin. The couplings ofthe amino acids are carried out by treating the resin for 1 hour with250 μmol of the suitably protected amino acid in the presence of 250μmol of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronimum,tetramethyluronium, hexafluorophosphate (BTUH), 250 ∞mol ofN-hydoxybenzotriazole and 750 μmol of diisopropylethylamine in 1.2 cm³of an N-methyl-2-pyrrolidone (NMP)/dimethylformamide (1/1 by volume)mixture. Deprotection of the FMOC group is carried out with 3 successivetreatments of the resin for 2 times 1 minute and then 20 minutes with 2cm³ of piperidine as a 2% (v/v) solution in NMP.

For example, Cys-(NMe)Val- cis-3-phenyl-DL-prolyl!-Met can be preparedin the following way:

50 μmol of Fmoc-Met-chlorotrityl resin are successively subjected to thefollowing treatments:

deprotection of the FMOC group,

washing with 5 times 2 cm³ of NMP,

coupling of FMOC-cis-3-phenyl-DL-proline,

washing with 5 times 2 cm³ of NMP,

deprotection of the FMOC group,

washing with 5 times 2 cm³ of NMP,

coupling of FMOC-N-methylvaline,

washing with 5 times 2 cm³ of NMP,

deprotection of the FMOC group,

washing with 5 times 2 cm³ of NMP,

coupling of FMOC-cysteine(S-trityl),

washing with 5 times 2 cm³ of NMP,

deprotection of the FMOC group,

washing with 5 times 2 cm³ of NMP.

On completion of the synthesis, the products are separated by treatmentof-the resin with 10 cm³ of a trifluoroaceticacid/phenol/ethanedithiol/thioanisole/-water (40/3/1/2/2 by volume)mixture for 1 hour 30 minutes. The resin is then removed by filtration.The filtrate is concentrated under reduced pressure by means of acentrifugal evaporator (RC10-10 Jouan) equipped with a vane pump andwith a trap at -90° C. for 1.5 hours, the temperature of the evaporationchamber being maintained at 50° C. The final volume of the concentrateis approximately 1 cm³. The product is then precipitated by addition of15 cm³ of a mixture of methyl tert-butyl ether and petroleum ether (2/1by volume) and it is then collected by centrifuging. The pellet is thendissolved in 1 cm³ of trifluoroacetic acid, precipitated by addition of15 cm³ of methyl tert-butyl ether and then washed with 15 cm³ of methyltert-butyl ether. The product is then dried under reduced pressure (3.5kPa). The product is finally purified by high performance liquidchromatography (HPLC) on a C₁₈ 100 Å column (250×10 mm, BioRad) elutedwith a gradient of acetonitrile containing 0.07% of trifluoroacetic acid(by volume) in water containing 0.07% of trifluoroacetic acid (byvolume) at a flow rate of 6 cm³ /min and then lyophilized. The productsobtained are characterized by their mass spectra (electrospray).

Introduction of the FMOC protective group onto an amino acid is carriedout by reaction of the amino acid with 9-fluorenylmethyl chloroformate(FMOC-chloride) in the presence of a base.

The FMOC-Met-chlorotrityl resin can be obtained by reaction of 250 μmolof chlorotrityl chloride resin (Novabiochem®) with 1 mmol ofFMOC-Methionine in 2 cm³ of dichloromethane and 0.5 cm³ ofdiisopropylethylamine for 30 minutes. After addition of 2 cm³ ofmethanol, the reaction is continued for a further 30 minutes. The resinis then washed with 5 times 4 cm³ of dichloromethane and then dried.

The cis- and trans-phenylprolines, in the racemic form, can be obtainedunder the conditions described by R. Sarges and J. R. Tretter, J. Org.Chem., 39, 1710 (1974).

The inhibitory activity with respect to farnesyl transferase and tofarnesylation of the Ras protein may be demonstrated in the followingtest:

Farnesyl transferase activity is determined by the quantity of ³H!farnesyl transferred from ³ H!farnesyl pyrophosphate ³ H!FPP) to thep21 H-ras protein. The standard reaction mixture is composed, for afinal volume of 60 μl, of 50 mM Tris-HCl, 5 mM MgCl₂, 5 mMdithiotreitol, 0.2% octyl β-D-glucopyranoside, 200 picomol p21 H-ras,4.5 picomol ³ H!FPP (activity 61000 dpm/picomol).

Reaction is initiated by adding approximately 5 ng of human farnesyltransferase purified from THP1 cell cultures. After incubation for 20minutes at 37° C. in a microtitration plate containing 96 1-cm³ wellsper plate (Titer Plate®, Beckman), the reaction is stopped by adding 0.4cm³ of 0.1% SDS in methanol at 0° C. The mixture is then treated with0.4 cm³ of 30% trichloroacetic acid® (TCA) in methanol. The plates areleft in ice for 1 hour. The precipitated contents are then retained onFiltermat®, Pharmacia) glass fibres membranes with the filtration unit(Combi Cell Harvester®, Skatron), and rinsed with 6% trichloroaceticacid in distilled water. The membranes are dried in a microwave oven,then impregnated with scintillation medium by melting Meltilex®(Pharmacia) under hot air, and lastly counted in cpm in a β-Plate®counter (LKB). Each test is repeated 3 times.

The unit of activity is defined as 1 picomol of ³ H!FPP transferred top21 H-ras in 20 minutes.

The percentage inhibition values are obtained by comparison of the testswith and without inhibitor after deduction of blanks, the IC₅₀ valuesbeing measured on the basis of the inhibitions obtained with 9 differentconcentrations using Enzfitter® or Grafit® software.

The results obtained are collated in Table I.

                  TABLE I    ______________________________________                           Inhibitory                           activity    Product                IC.sub.50    ______________________________________    Cys-(N-Me)Val- cis-3-phenyl-DL-prolyl!-Met                           1.55 × 10.sup.-8 M    Cys-(N-Me)Val- trans-3-phenyl-DL-prolyl!-Met                            9.2 × 10.sup.-7 M    ______________________________________

The new peptides of general formula (I) can be in the form of non-toxicand pharmaceutically acceptable salts. These non-toxic salts comprisethe salts with inorganic acids (hydrochloric, sulphuric, hydrobromic,phosphoric and nitric acids) or with organic acids (acetic, propionic,succinic, maleic, hydroxymaleic, benzoic, fumaric, methanesulphonic,trifluoroacetic or oxalic acid), or with inorganic bases (sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide) ororganic bases (tertiary amines such as triethylamine, piperidine,benzylamine), depending on the nature of the constituent amino acids ofthe peptide of general formula (I).

The new peptides according to the invention, which inhibit farnesyltransferase and farnesylation of the Ras protein, are notable anticanceragents which are active as regards both solid and non-solid tumours.

The present invention also relates to pharmaceutical compositionscontaining at least one peptide of general formula (I), in combinationwith one or more pharmaceutically acceptable diluents or adjuvants,which may be either inert or physiologically active.

These compositions may be administered orally, parenterally or rectally.

The compositions for-oral administration comprise tablets, pills,powders or granules. In these compositions, the active product accordingto the invention is mixed with one or more inert diluents such assucrose, lactose or starch. These compositions can comprise substancesother than diluents, for example lubricants such as magnesium stearate.

As liquid compositions for oral administration, solutions, suspensions,syrups, elixirs and pharmaceutically acceptable emulsions, containinginert diluents such as water or liquid paraffin, may be used. Thesecompositions can also comprise substances other than diluents, forexample wetting, sweetening or flavouring products.

The compositions according to the invention for parenteraladministration can be sterile solutions, aqueous or non-aqueous,suspensions or emulsions. As solvent or vehicle, propylene glycol, apolyethylene glycol, vegetable oils, especially olive oil, or injectableorganic esters, for example ethyl oleate, may be employed. Thesecompositions can also contain adjuvants, especially wetting, emulsifyingand dispersing agents. The sterilization may be carried out in severalways, for example using a bacteriological filter, by incorporatingsterilizing agents in the composition or by heating. They may also beprepared in the form of sterile solid compositions which can bedissolved at the time of use in sterile water or any other sterileinjectable medium.

The compositions for rectal administration are suppositories which cancontain, besides the active product, excipients such as cocoa butter.

The compositions according to the invention are especially useful inhuman therapy in the treatment of cancers of various origins.

In human therapy, the doses depend on the effect sought, the period oftreatment and factors specific to the subject to be treated.

Generally, in man, the doses are between 0.1 and 20 mg/kg per day viathe intraperitoneal route.

I claim:
 1. A compound of formula: ##STR5## in which: R₁ represents aradical of formula Y--S--A₁ --;Y represents a hydrogen atom, an aminoacid residue, a fatty acid residue, an alkyl radical, an alkoxycarbonylradical or a R₄ --S-- radical; R₄ represents an alkyl radical of 1 to 6carbon atoms, optionally substituted by a phenyl radical, or a radicalof formula ##STR6## A₁ represents a straight or branched alkyleneradical of 1 to 4 carbon atoms, optionally substituted at the position αto the >C(X₁)(Y₁) group by an amino radical, an alkylamino radical of 1to 4 carbon atoms, an alkanoylamino radical of 1 to 4 carbon atoms or analkoxycarbonylamino radical in which the alkyl part is of 1 to 4 carbonatoms; X₁ and Y₁ each represent a hydrogen atom or form, together withthe carbon atom to which they are bonded, a >C═O group; R₂ represents astraight or branched alkyl radical of 1 to 4 carbon atoms, optionallysubstituted by a cyclohexyl radical; R'₂ represents a hydrogen atom or astraight or branched alkyl radical of 1 to 6 carbon atoms; X₂ and Y₂each represent a hydrogen atom or form, together with the carbon atom towhich they are bonded, a >C═O group; R₃ represents a straight orbranched containing alkyl radical of 1 to 4 carbon atoms, optionallysubstituted by a hydroxyl radical, an alkoxy radical of 1 to 4 carbonatoms, a mercapto radical, an alkylthio radical of 1 to 4 carbon atoms,an alkylsulphinyl radical of 1 to 4 carbon atoms or an alkylsulphonylradical of 1 to 4 carbon atoms, wherein, when R₃ represents ahydroxyalkyl radical, R₃ can form a lactone with the carboxyl radical atthe α position; R'₃ represents a hydrogen atom or a straight or branchedalkyl radical of 1 to 6 carbon atoms; X represents an oxygen or sulphuratom; and R represents a hydrogen atom or an alkyl radical, optionallysubstituted by an alkoxy radical of 1 to 4 carbon atoms, an alkylthioradical of 1 to 4 carbon atoms, an alkylsulphinyl radical of 1 to 4carbon atoms, an alkylsulphonyl radical of 1 to 4 carbon atoms, aphenoxy radical, a phenylthio radical, a phenylsulphinyl radical, aphenylsulphonyl radical, an alkylamino radical of 1 to 4 carbon atoms ora dialkylamino radical in which each alkyl group is of 1 to 4 carbonatoms, or a phenyl radical, optionally substituted by at least one atomor radical, independently selected from the group consisting of ahalogen atom, an alkyl radical of 1 to 4 carbon atoms, an alkoxy radicalof 1 to 4 carbon atoms, an alkylthio radical of 1 to 4 carbon atoms, andalkanoyl radical of 1 to 4 carbon atoms; or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1, in whichR₁ represents a radical of formula Y--S--A₁ --;Y represents a hydrogenatom, a lysine residue, or a fatty acid residue containing up to 20carbon atoms; A₁ represents an ethylene or propylene radical optionallysubstituted by an amino radical; X₁ and Y₁ each represent a hydrogenatom or form, together with the carbon atom to which they are bonded,a >C═O group; R₂ represents an isopropyl radical, a 1-methylpropylradical, a teit-butyl radical or a cyclohexylmethyl radical; R'₂represents a hydrogen atom or a methyl radical; X₂ and Y₂ each representa hydrogen atom or form, together with the carbon atom to which they arebonded, a >C═O group; R₃ represents a methyl or ethyl radicalsubstituted by a hydroxyl, methoxy, mercapto, methylthio,methylsulphinyl or methylsulphonyl radical; R'₃ represents a hydrogenatom or a methyl radical; X represents an oxygen atom; and R representsa hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms,optionally substituted by an alkoxy radical, or a phenyl radical; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1, in which R₁ represents a radical of formula Y--S--A₁ --;Yrepresents a hydrogen atom; A₁ represents an ethylene or propyleneradical optionally substituted by an amino radical; X₁ and Y₁ eachrepresent a hydrogen atom or form, together with the carbon atom towhich they are bonded, a >CO group; R₂ represents a isopropyl radical, a1-methylpropyl radical, a tert-butyl radical or a cyclohexylmethylradical; R'₂ represents a hydrogen atom; X₂ and Y₂ each represent ahydrogen atom or form, together with the carbon atom to which they arebonded, a >C═O group; R₃ represents a methyl or ethyl radicalsubstituted by a hydroxyl, methoxy, mercapto or methylthio radical; R'₃represents a hydrogen atom; and R represents a hydrogen atom or an alkylradical containing 1 to 4 carbon atoms; or a pharmaceutically acceptablesalt thereof.
 4. The compound according to claim 1, in which R₁represents a 2-mercaptoethyl or 1-amino-2-mercaptoethyl radical;X₁ andY₁ each represent a hydrogen atom or form, together with the carbon atomto which they are bonded, a >CO group; R₂ represents an isopropylradical; X₂ and Y₂ each represent a hydrogen atom or form, together withthe carbon atom to which they are bonded, a >C═O group; R'₂ represents ahydrogen atom; R₃ represents a 2-(methylthio)ethyl or2-(methylsulphinyl)ethyl radical; R'₃ represents a hydrogen atom; and Rrepresents a hydrogen atom; or a pharmaceutically acceptable saltthereof.
 5. The compound according to claim 1 wherein R₁ C(X₁)(Y₁), R₂CH (NR'₂) C(X₁)(Y₂)! and R₃ CH(NR'₃)COOH moieties represent amino acidresidues which are independently of the L or D configuration.
 6. Thecompound according to claim 5 wherein each amino acid residue is of theD configuration.
 7. The compound according to claim 5 wherein each aminoacid residue is of the L configuration.
 8. A compound selected from thegroup consisting ofCys-(N-Me)Val- cis-3-phenyl-D-prolyl!-Met;Cys-(N-Me)Val- cis-3-phenyl-L-prolyl!-Met; Cys-(N-Me)Val-trans-3-phenyl-D-prolyl!-Met; and Cys-(N-Me)Val-trans-3-phenyl-L-prolyl!-Met.
 9. A mixture of diastereomerscomprisingCys-(N-Me)Val- cis-3-phenyl-D-prolyl!-Met and Cys-(N-Me)Val-cis-3-phenyl-L-prolyl!-Met.
 10. A mixture of diastereomerscomprisingCys-(N-Me)Val- trans-3-phenyl-D-prolyl!-Met and Cys-(N-Me)Val-trans -3-phenyl-L-prolyl!-Met.
 11. A pharmaceutical compositioncomprising a pharmaceutically acceptable amount of a compound accordingto claim 1 and an inert or physiologically active pharmaceuticallyacceptable diluent or adjuvant.
 12. A method of inhibiting farnesyltransferase in a patient, comprising administering to a patient atherapeutically effective dose of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 13. A method of inhibitingfarnesyl transferase, comprising contacting a farnesyl transferaseinhibitory amount of a compound according to claim 1, or a salt thereofwith a composition containing farnesyl transferase.
 14. A method fortreating cancer, caused by mutated ras protein, in a patient comprisingadministering to the patient a therapeutically effective dose of acompound according to claim 1, or a pharmaceutically acceptable saltthereof.
 15. A method for cancer therapy, wherein the cancer isassociated with famesyl transferase activity, comprising administeringto a patient in need of such therapy a therapeutically effective amountof a compound according to claim 1, or a pharmaceutically acceptablesalt thereof.
 16. A method for treating cancer in a patient, comprisingadministering to the patient a therapeutically effective dose of acompound according to claim 1, or a pharmaceutically acceptable saltthereof.
 17. The method according to claim 16 wherein the administeringis oral, parenteral or rectal.
 18. The method according to claim 16wherein the therapeutically effective dose is between 0.1 and 20 mg/kgper day.